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Studies directed at the use of a parallel synthesis matrix to increase throughput in an in vivo assay.

机译:研究针对在体内测定中使用平行合成基质以增加通量。

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Heparin is the anticoagulant of choice for hospitalized patients, but it is dosed only by injection because it is not absorbed following oral administration. We have discovered and prepared compounds (delivery agents) that facilitate the gastrointestinal absorption of heparin in rats, monkeys, and humans when given orally. We are currently developing a parallel synthesis approach to increase our delivery agent screening throughput in vivo. This approach has been used to produce micromolar quantities of compounds for testing in rats in a 5 x 5 parallel synthesis array. Using an amine benzoylation reaction sequence, 10 mixtures were prepared. These mixtures contained equal weight quantities of five N-substituted, non-alpha, amino acid delivery agents. Each of these mixtures was orally administered to rats in combination with heparin, and plasma clotting times (APTT) were measured to determine activity. Deconvolution of the data accurately identified the most active individual components. Independent synthesis of these compounds verified their activity. This parallel synthesis approach is an effective tool for the screening of oral heparin delivery agents and has increased screening throughput significantly.
机译:肝素是住院患者的首选抗凝剂,但只能口服注射,因为口服后它不会被吸收。我们已经发现并制备了口服给药时可促进大鼠,猴子和人类中肝素胃肠道吸收的化合物(输送剂)。我们目前正在开发一种平行合成方法,以提高体内的递送剂筛选效率。该方法已用于生产微摩尔量的化合物,以5 x 5平行合成阵列在大鼠中进行测试。使用胺苯甲酰化反应序列,制备了10种混合物。这些混合物包含等重量的五种N-取代的非α-氨基酸递送剂。将这些混合物中的每一种与肝素组合口服给予大鼠,并测量血浆凝结时间(APTT)以确定活性。对数据进行反卷积可准确识别出最活跃的单个组件。这些化合物的独立合成证实了它们的活性。这种平行合成方法是筛选口服肝素递送剂的有效工具,并且显着提高了筛选通量。

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